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The Journal of Neuroscience, July 18, 2007, 27(29):7731-7739; doi:10.1523/JNEUROSCI.1736-07.2007
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Behavioral/Systems/Cognitive
Transient Overexpression of Striatal D2 Receptors Impairs Operant Motivation and Interval Timing
Michael R. Drew,1,2 Eleanor H. Simpson,3 Christoph Kellendonk,3 William G. Herzberg,2,6 Olga Lipatova,2,6 Stephen Fairhurst,2,7 Eric R. Kandel,3,4,5,7 Chara Malapani,2,7 andPeter D. Balsam2,6 1Division of Integrative Neuroscience, Department of Psychiatry, 2Biopsychology Unit, Department of Psychiatry, 3Center for Neurobiology and Behavior, 4Howard Hughes Medical Institute, 5Kavli Institute for Brain Science, College of Physicians and Surgeons of Columbia University, New York, New York, 10032, 6Barnard College, Columbia University, New York, New York 10027, and 7New York State Psychiatric Institute, New York, New York 10032
Correspondence should be addressed to Dr. Michael R. Drew, 1051 Riverside Drive, Unit 87, Kolb Annex Room 767, New York, NY 10032. Email: mrd28{at}columbia.edu
The striatum receives prominent dopaminergic innervation that is integral to appetitive learning, performance, and motivation. Signaling through the dopamine D2 receptor is critical for all of these processes. For instance, drugs with high affinity for the D2 receptor potently alter timing of operant responses and modulate motivation. Recently, in an attempt to model a genetic abnormality encountered in schizophrenia, mice were generated that reversibly overexpress D2 receptors specifically in the striatum (Kellendonk et al., 2006). These mice have impairments in working memory and behavioral flexibility, components of the cognitive symptoms of schizophrenia, that are not rescued when D2 overexpression is reversed in the adult. Here we report that overexpression of striatal D2 receptors also profoundly affects operant performance, a potential index of negative symptoms. Mice overexpressing D2 exhibited impairments in the ability to time food rewards in an operant interval timing task and reduced motivation to lever press for food reward in both the operant timing task and a progressive ratio schedule of reinforcement. The motivational deficit, but not the timing deficit, was rescued in adult mice by reversing D2 overexpression with doxycycline. These results suggest that early D2 overexpression alters the organization of interval timing circuits and confirms that striatal D2 signaling in the adult regulates motivational process. Moreover, overexpression of D2 under pathological conditions such as schizophrenia and Parkinson's disease could give rise to motivational and timing deficits.
Key words: learning; schizophrenia; Parkinson's disease; dopamine; basal ganglia; conditioning
Received April 17, 2007; revised June 5, 2007; accepted June 6, 2007.
Correspondence should be addressed to Dr. Michael R. Drew, 1051 Riverside Drive, Unit 87, Kolb Annex Room 767, New York, NY 10032. Email: mrd28{at}columbia.edu
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[Abstract] [Full Text] [PDF]
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